New target therapies in prostate cancer: from radioligand therapy, to PARP-inhibitors and immunotherapy.

Prostate cancer (PCa) remains a significant global health challenge, particularly in its advanced stages. Despite progress in early detection and treatment, PCa is the second most common cancer diagnosis among men. This review aims to provide an overview of current therapeutic approaches and innovations in PCa management, focusing on the latest advancements and ongoing challenges. We conducted a narrative review of clinical trials and research studies, focusing on PARP inhibitors (PARPis), phosphoinositide 3 kinase-protein kinase B inhibitors, immunotherapy, and radioligand therapies (RLTs). Data was sourced from major clinical trial databases and peer-reviewed journals. Androgen deprivation therapy and androgen-receptor pathway inhibitors remain foundational in managing castration-sensitive and early-stage castration-resistant PCa (CRPC). PARPi's, such as olaparib and rucaparib, have emerged as vital treatments for metastatic CRPC with homologous recombination repair gene mutations, highlighting the importance of personalized medicine. Immune checkpoint inhibitors (ICIs) have shown clinical benefit limited to specific subgroups of PCa, demonstrating significant improvement in efficacy in patients with microsatellite instability/mismatch repair or cyclin-dependent kinase 12 alteration, highlighting the importance of focusing ongoing research on identifying and characterizing these subgroups to maximize the clinical benefits of ICIs. RLTs have shown effectiveness in treating mCRPC. Different alpha emitters (like [225Ac]PSMA) and beta emitters compounds (like [177Lu]PSMA) impact treatment differently due to their energy transfer characteristics. Clinical trials like VISION and TheraP have demonstrated positive outcomes with RLT, particularly [177Lu]PSMA-617, leading to FDA approval. Ongoing trials and future perspectives explore the potential of [225Ac]PSMA, aiming to improve outcomes for patients with mCRPC. The landscape of PCa treatment is evolving, with significant advancements in both established and novel therapies. The combination of hormonal therapies, chemotherapy, PARPis, immunotherapy, and RLTs, guided by genetic and molecular insights, opens new possibilities for personalized treatment.

Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs.

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

Thymic Epithelial Tumor and Immune System: The Role of Immunotherapy.

Thymic epithelial tumors (TETs) comprise a rare group of thoracic cancers, classified as thymomas and thymic carcinomas (TC). To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory tumors. Unlike other solid cancers, the development of targeted biologic and/or immunologic therapies in TETs remains in its nascent stages. Moreover, since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology, which can confer susceptibility to autoimmune diseases and ultimately influence the risk-benefit balance of immunotherapy, especially for patients with thymoma. Indeed, early results from single-arm studies have shown interesting clinical activity, albeit at a cost of a higher incidence of immune-related side effects. The lack of knowledge of the immune mechanisms associated with TETs and the absence of biomarkers predictive of response or toxicity to immunotherapy risk limiting the evolution of immunotherapeutic strategies for managing these rare tumors. The aim of this review is to summarize the existing literature about the thymus's immune biology and its association with autoimmune paraneoplastic diseases, as well as the results of the available studies with immune checkpoint inhibitors and cancer vaccines.

Rituximab in steroid-refractory immune-related pancreatitis: a case report.

The use of immune checkpoint inhibitors (ICIs) for treating several types of cancer is increasing, but they may be associated with immune-related adverse events (irAEs). Pancreatitis is a rare irAE, mostly responsive to steroid treatment. There are no published data on the management of steroid-refractory ICI-induced pancreatitis. Rituximab has shown efficacy in the setting of relapsing non-ICI-induced autoimmune pancreatitis. However, its use has not been tested for treating immunotherapy-related pancreatitis. Here, we present the case of a patient with steroid-refractory immune-related pancreatitis successfully treated with rituximab as a potential strategy for irAE management.

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress.

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient's selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated. In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.

Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.

Advances in drug treatments for mesothelioma.

INTRODUCTION: The paucity of the therapeutic armamentarium currently available for patients with malignant mesothelioma clearly represents a huge unmet need. Over the last years, based on new advances in understanding the biology of mesothelioma, new therapeutic approaches have been investigated. AREAS COVERED: In this manuscript, the literature data regarding the advances in drug treatment for patients with mesothelioma are critically reviewed, focusing particularly on immunotherapy and targeted therapy. EXPERT OPINION: The latest findings on immunotherapy and targeted therapy are changing the therapeutic armamentarium for mesothelioma. However, mesothelioma comprises genomically different subtypes and the phenotypic diversity combined with the rarity of this disease represents a major criticality in developing new effective therapies. Although the first clinical data are encouraging, the treatment's stratification by molecular characteristics for mesothelioma is only at the beginning. Luckily, the rapid improvement of understanding the biology of mesothelioma is producing new opportunities in discovering new therapeutic targets to test in pre-clinical settings and to transfer in the clinical setting. In this evolving scenario, the future perspectives for mesothelioma patients seem really promising.

Oligoprogressive castration-resistant prostate cancer treated with metastases-directed stereotactic body radiation therapy: predictive factors for patients' selection.

Oligoprogression is defined as limited metastatic clone resistant to on-going systemic treatment that grows in a background of stable or responding systemic disease. Aim of the present study was to analyze oligoprogressive prostate cancer (PC) patients treated with stereotactic body radiation therapy (SBRT) during systemic treatment to identify predictive factors and improve patients' selection. We included PC patients treated with SBRT on a maximum of 3 sites of oligoprogression during systemic therapy. Endpoints were freedom from polymetastatic progression (FPP), local control (LC), distant progression free survival (DPFS), overall survival (OS), and next systemic therapy free survival (NEST-FS). Fifty-three patients were treated on 85 oligoprogressive metastases. Lymph nodes were the most common sites (56.47%), followed by bone (39.29%). Median follow-up was 24.9 months. Rates of FPP at 1- and 2-year were 80.1% and 68.9%, respectively. Median time to polymetastatic progression was 33.7 months. Disease free interval (p = 0.004), site of metastases (p = 0.011), and type of systemic therapy (p = 0.003) were significant for FPP. Switch or intensification of systemic therapy after SBRT was observed in 29 (54.72%) patients with a median NEST-FS of 15.2 months. LC at 1- and 2-year was 94.0% and 92.0%, with PSA doubling time resulted to be significantly associated (p = 0.047). Median DPFS was 8.93 months and median OS was 50.6 months. In conclusion, we confirmed the efficacy of SBRT for oligoprogression from PC, with the potential to prolong the on-going systemic therapy and interrupt the metastatic cascade.

Resound Trial: A phase 2 study of regorafenib in patients with thymoma (type B2-B3) and thymic carcinoma previously treated with chemotherapy.

BACKGROUND: Angiogenesis has an important role in thymic epithelial tumors (TETs). Regorafenib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor ß (PDGFR-ß), and fibroblast growth factor receptors (FGFRs). This study explored the activity of regorafenib as monotherapy in patients with advanced or recurrent B2-B3 thymoma (T) and thymic carcinoma (TC) previously treated with platinum-containing chemotherapy. METHODS: A Fleming single-arm, single-stage, phase 2 trial to evaluate the activity of regorafenib (160 mg once a day by mouth for 3 weeks on/1 week off) was planned. The study was designed to reject the null hypothesis of an 8-week progression-free survival (PFS) rate ≤25% with a type I error of 0.10 and a statistical power of 80% at the alternative hypothesis of an 8-week PFS rate of ≥50% (≥8 of 19 evaluable patients progression-free at 2 months). RESULTS: From June 2016 to November 2017, 19 patients were enrolled (11T/8TC). We observed partial response (PR) in 1 patient (1T) (5.3%), stable disease (SD) in 14 patients (9T/5TC) (73.7%), and progressive disease in 2 patients (1T/1TC) (10.5%), with a disease control rate of 78.9%. According to Choi-criteria, 13 patients (68.4%) achieved PR, and 2 patients SD (10.5%). The median PFS was 9.6 months whereas median overall survival was 33.8 months. The 8-week PFS rate was 78.9% (15 of 19 patients). Grade 3-4 treatment-related adverse events were observed in 10 patients (52.6%). CONCLUSIONS: The primary end point of this study was reached. The high rate of PR (Choi-criteria) suggests antitumor activity of regorafenib in TETs. On the basis of survival outcomes, the efficacy of regorafenib should be further evaluated in larger studies.

Systemic treatments for thymic tumors: a narrative review.

Thymic epithelial tumours (TETs) are rare tumours originating from the thymus. Considering the rarity of this disease, the management of TETs is still challenging and difficult. In fact, all the worldwide clinical practice guidelines are based on data from retrospective analyses, prospective single arm trials or experts' opinions. The results of combined modality therapy (chemotherapy, surgery, radiotherapy) in thymic malignancies are reasonably good in less advanced cases whereas in case of advanced (unsuitable for surgery) or metastatic disease, a platinum-based chemotherapy is considered standard of care. Unfortunately, chemotherapy in the palliative setting has modest efficacy. Moreover, due to the lack of known oncogenic molecular alterations, no targeted therapy has been shown to be efficient for these tumours. In order to offer the best diagnostic and therapeutic tools, patients with TETs should be managed with a continuous and specific multidisciplinary expertise at any step of the disease, especially in the era of a novel coronavirus disease (COVID-19). Current evidences show that cancer patients might have more severe symptoms and poorer outcomes from COVID-19 infection than general population. With the exception of the patients carrying a Good's syndrome, there is no evidence that patients with TETs present a higher risk of infection compared with other cancer patients and their management should be the same. The aim of this review is to summarize the existing literature about systemic treatments for TETs in all clinical setting (local and locally advanced/metastatic disease) exploring how these therapeutic strategies have been managed in the COVID-19 era.

Current Perspectives on Immunotherapy in the Peri-Operative Setting of Muscle-Infiltrating Bladder Cancer.

Patients with muscle-infiltrating bladder cancer (MIBC) present a high risk of postoperative recurrence and death from metastatic urothelial cancer despite surgical resection. Before the use of peri-operative chemotherapy, about half (52%) of patients undergoing radical cystectomy had had a relapse of tumor disease within 5 years of surgery. However, when peri-operative cisplatin-based chemotherapy is added to radical cystectomy for patients with MIBC it provides limited benefit in terms of survival, disease recurrence and development of metastases, at the expense of toxic effects. In fact, a significant proportion of patients still recurs and die to metastatic disease. Given the success of immune-oncological drugs in metastatic urothelial cancer, several trials started to test them in patients with non-metastatic MIBC either in neo-adjuvant and adjuvant setting. The preliminary results of these studies in neo-adjuvant setting are showing great promise, confirming the potential benefits of immunotherapy also in patients with non-metastatic MIBC. The aim of this review is to present an overview of developments happening on the introduction of immunotherapy in peri-operative setting in non-metastatic urothelial cancer. Moreover, an analysis of the critical issues regarding how best customize the delivery of immunotherapy to optimize efficacy and minimize the adverse effects, with particular focus on potential prognostic and predictive molecular biomarkers, is done.

A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma.

OBJECTIVES: Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-ß and/or cKIT by immunohistochemistry (IHC). PATIENTS AND METHODS: GEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS). RESULTS: In total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients. CONCLUSIONS: The combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-ß and/or cKIT by IHC, but it does not show a significant PFS benefit.

Pulmonary sarcomatoid carcinoma presenting both ALK rearrangement and PD-L1 high positivity: A case report on the therapeutic regimen.

RATIONALE: Pulmonary sarcomatoid carcinoma (PSC) represents <1% of all lung cancers and is characterized by a very poor prognosis. The optimal therapeutic regimen remains unclear. We describe a rare case of PSC with both anaplastic lymphoma kinase (ALK)-arranged and high levels of programmed death ligand 1 (PD-L1) expression. PATIENT CONCERNS: A 46-year-old woman, nonsmoker, came to our attention due to uncontrolled pain in the lower left limb. DIAGNOSIS: PSC with both ALK rearrangement and high levels of PD-L1 expression. INTERVENTIONS: The patient started first-line systemic treatment with pembrolizumab reporting stable disease; at progression, she received second-line treatment with crizotinib. The treatment was not well-tolerated, and the patient then underwent 5 cycles of ceritinib treatment. OUTCOMES: The patient showed a partial response to targeted therapy. At progression, brigatinib was initiated, but the patients reported liver progression soon after the initiation of this therapy. LESSONS: Molecular-driven investigation is necessary in PSC for treatment selection.

Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy.

Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin-containing chemotherapy. Patients and Methods This was a single-arm, single-stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (α = ß = 0.10): If disease control were achieved in ≥ 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E-BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis.

Prognostic and predictive role of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy.

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG-PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed-based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first-line pemetrexed-based chemotherapy, and evaluated by FDG-PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were correlated with FDG-PET parameters, such as maximum standardized uptake value (SUVmax ), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG-PET in a large series of MPM patients treated with first-line pemetrexed-based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut-off values to define early metabolic response supported the role of FDG-PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.

Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study.

We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies.

Prognostic factors in patients receiving third line targeted therapy for metastatic renal cell carcinoma.

PURPOSE: Several prognostic models have been proposed for metastatic renal cell carcinoma but none has been validated in patients who receive third line targeted agents. We evaluated prognostic factors in patients with metastatic renal cell carcinoma who received a third line targeted agent. MATERIALS AND METHODS: We retrospectively reviewed data on 2,065 patients with clear cell metastatic renal cell carcinoma who were treated with targeted therapy at a total of 23 centers in Italy. Included in final analysis were 281 patients treated with 3 targeted agents. Overall survival was the main outcome. Cox proportional hazards regression followed by bootstrap validation was used to identify independent prognostic factors. RESULTS: Three clinical characteristics (ECOG performance status greater than 1, metastasis at diagnosis and liver metastasis) and 2 biochemical factors (hemoglobin less than the lower limit of normal and neutrophil count greater than the upper limit of normal, respectively) were prognostic. Patients were classified into 3 risk categories, including low-zero or 1, intermediate-2 and high risk-more than 2 risk factors. Median overall survival was 19.7, 10.1 and 5.5 months, and 1-year overall survival was 71%, 43% and 15%, respectively. The major limitation was the retrospective nature of this study and absent external validation. CONCLUSIONS: This nomogram included clinical and biochemical prognostic factors. In clinical trials it may be useful to select patients and define the prognosis.

Lymphopenia and clinical outcome of elderly patients treated with sunitinib for metastatic renal cell cancer.

OBJECTIVE: Lymphopenia is associated with toxicity and outcomes in several cancer types. We assessed the association between pre-treatment lymphopenia, toxicity, and clinical outcomes in elderly patients with metastatic renal cell cancer (mRCC) treated with first-line sunitinib. Prognostic factors in these patients were also evaluated. PATIENTS AND METHODS: We reviewed the clinical records of 181 patients with mRCC aged ≥70 years treated with first-line sunitinib in 17 Italian Oncology Units from February 2006 to September 2011. Baseline lymphopenia was defined as lymphocyte counts <1000/µL. RESULTS: Twenty-nine (16%) patients had a baseline lymphocyte count <1000/µL (group A) and 152 (84%) patients had a lymphocyte count ≥1000/µL (group B). Although no differences between the two groups were reported in terms of overall response rate (P = 0.207), dose reductions (P = 0.740), discontinuation due to adverse events (P = 0.175) or overall incidence of grade 3-4 toxicities (P = 0.112), more patients in the lymphopenia group had grade 3-4 neutropenia (P = 0.017), grade 3-4 thrombocytopenia (P = 0.017) and grade 3-4 diarrhea (P = 0.006). In multivariate analysis, performance status and Heng score were predictors of progression-free survival (P = 0.015 and P = 0.0006, respectively), while performance status, Heng score, and lymphopenia were found to be significantly associated with overall survival (P = 0.007, P < 0.0001 and P = 0.023, respectively). CONCLUSIONS: Sunitinib appears to be safe and active in elderly patients with lymphopenia. Lymphocyte count is an independent prognostic factor for overall survival in elderly patients with mRCC treated with first-line sunitinib.

Standard vs adapted sunitinib regimen in elderly patients with metastatic renal cell cancer: results from a large retrospective analysis.

BACKGROUND: There are no data on the patterns of care and outcome of elderly patients with mRCC treated with sunitinib. In a retrospective study, we assessed the routine use of first-line sunitinib in mRCC patients aged ≥ 70 years. PATIENTS AND METHODS: We reviewed the clinical files of 185 patients aged ≥ 70 years with mRCC treated with first-line sunitinib in 17 Italian oncology units from February 2006 to September 2011. One hundred twenty-three patients (66.5%) received a standard 50 mg/d for a 4 weeks on/2 weeks off regimen (SR), and 62 patients (33.5%) received an AR consisting of 37.5 mg/d for a 4 weeks on/2 weeks off in 67.7% of cases. RESULTS: Median age was 74 years. Patients treated with an AR were older than those treated with the SR (P < .0001). In the overall population, the median progression-free survival (PFS) was 11 months, and the median overall survival (OS) was 25.5 months. Grade 3-4 toxicities occurred in 87 of 123 SR (70.7%) and 32 of 62 AR (51.6%), respectively; dose reductions were required in 82 SR (66.7%) and 26 AR (41.9%), respectively; discontinuations because of therapy-related adverse events occurred in 25 SR (20.3%) and 15 AR (24.2%), respectively. In multivariate analysis, only performance status and the Heng score were predictors of either PFS or OS. CONCLUSION: Sunitinib is active and feasible in elderly patients with mRCC. A sunitinib AR could be considered as an option in selected older mRCC patients. The optimal treatment of frail patients with mRCC remains to be established.

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: results from a large patient cohort.

AIM: A number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome. METHODS: Patients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS)--defined as the time from start of first-line to progression on third-line treatment--were estimated using the Kaplan-Meier method and curves were compared with log-rank test. RESULTS: A total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)-VEGFi-mTORi compared with those receiving VEGFi-mTORi-VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively). CONCLUSIONS: Few patients received three lines of TTs. The sequence VEGFi-VEGFi-mTORi was associated with improved survival with respect to VEGFi-mTORi-VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.